Given the high frequency of genomic gain of TBC1D31 in HCCs (≈50%), our findings thereby provide an indicator of primary resistance to lenvatinib, and suggest a potential therapy strategy that simultaneously inhibits the TBC1D31‐EGFR axis when using lenvatinib in those HCC cases with TBC1D31 amplification. The gene discussed is TBC1D31; the disease is hepatocellular carcinoma.